Fampridine works in the real life situation

Macdonell R, Nagels G, Laplaud DA, Pozzilli C, de Jong B, Martins da Silva A, Nicholas R, Lechner-Scott J, Gaebler JA, Agarwal S, Wang P, Yeh M, Hovenden M, Soelberg Sørensen P.
Improved patient-reported health impact of multiple sclerosis: The ENABLE study of PR-fampridine. Mult Scler. 2015. pii: 1352458515606809. [Epub ahead of print]

BACKGROUND:Multiple sclerosis (MS) is a debilitating disease that negatively impacts patients’ lives.
OBJECTIVE: ENABLE assessed the effect of long-term prolonged-release (PR) fampridine (dalfampridine extended release in the United States) treatment on patient-perceived health impact in patients with MS with walking impairment.
METHODS:ENABLE was a 48-week, open-label, Phase 4 study of PR-fampridine 10 mg twice daily. Patients who showed any improvement in Timed 25-Foot Walk walking speed at weeks 2 and 4 and any improvement in 12-item MS Walking Scale score at week 4 remained on treatment. The primary endpoint was change from baseline in 36-Item Short-Form Health Survey (SF-36) physical component summary (PCS) score.
RESULTS: At week 4, 707/901 (78.5%) patients met the criteria to remain on treatment. Patients on treatment demonstrated significant and clinically meaningful improvements in SF-36 PCS scores from baseline (mean change (95% confidence interval)) to week 12 (4.30 (3.83, 4.78); p < 0.0001), week 24 (3.75 (3.23, 4.27); p < 0.0001), week 36 (3.46 (2.95, 3.97); p < 0.0001), and week 48 (3.24 (2.72, 3.77); p < 0.0001). Significant improvements from baseline were also demonstrated in secondary health measures in patients on treatment.
CONCLUSION:  PR-fampridine improved patient-perceived physical and psychological health impact of MS measured in a real-life setting.

Fampridine can improve walkng for some people, and this occurs in the real-life situation

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  • It seems that Fampridine has a positive clinical effect on MS patient, doesn't it? When do someone will try to use Fampridine as a DMT? You might tell me: "you are naive everybody knows that only immunisuppressive drugs really work against MS!". I would answer: "Backup this statement with an experimental proof or a solid clinical study showing its inefficiency. People call that doing Science".

    • You would have to come up with a plausible hypothesis why fampridine might act as a DMT rather than just mediating a pathological consequence of MS.

    • H1: make the oligodendrocytes more robust against the immune system, e.g. by promoting their multiplication. There might be a reason behind these people walking again, no? And come on, do you think James Lind had a valid hypothesis to start his clinical trial?

    • Competing with potassium channel-targeting immune response? Yes, I know a specific potassium channel as an antigen was not confirmed, but there may be others

    • As a theoretician I love model so let me propose something.

      A model on how I get MS. Let suppose that a virus has infected my
      oligodendrocytes (you like the viral origin, don't you?). A retro-virus that
      integrates itself in the genome of this cell type (maybe in a X chromosome).
      Initially the virus is unable to kill a cell by itself, so it is using the
      immune system as an ally. It makes the oligodendrocyte produce antigen that
      will tell to the immune system, "kill me". When the cell dies this way the
      virus happily propagates in other cells. At some point, it might not even need
      the immune system anymore. I hope this day will not come for me as it might
      mean turning from RRMS into a SPMS.

      This model has the advantage of explaining the good and bad outcome of
      immunomodulatory drugs. These drugs make the immune system weaker, so it be
      less likely to kill the oligodendrocyte. It also proposes an explanation for
      their limits, making the immune system does not stop the disease it does not
      cut the root of the problem. Being to weak in killing a cell might cause
      collateral effect like not be able to fight other opportunistic infections.
      One could also search confirmation of this model in how the disease spreads in
      time and space.

      A model has the value of its prediction, particularly predictions about new
      therapeutic targets. If this model is not too wrong, then finding a good
      agonist of the antigen responsible for the death of oligodendrocytes might be
      a good candidate. One could also imagine an antiviral that would block the
      spread of this virus when it is circulating out of the cell.

      This is where EAE can be crucially useful. What is the mechanism of EAE? It is
      a viral induction, isn't it?

    • The onset of the disease; the relapses-remitting cycle; the inefficiency of immunomodulator treatments in PPMS and SPMS. Maybe the autoimmune theory provide an explanation to these and I do not know about it, but I do not think so.

    • The onset of the disease is not much of a mystery for the autoimmune theory (at least no more so than for this proposal): the immune system encounters a novel pathogen which is structurally similar to some CNS protein, and some subset of immune cells become autoreactive.

      Relapsing-remitting cycle: this is a mystery under the autoimmune theory, though other autoimmune diseases (rheumatoid arthritis, lupus, Crohn's) also exhibit this pattern. Assuming that you believe these other diseases are autoimmune, this is evidence in favor of MS also being one, as it suggests that MS behaves like a typical autoimmune disease. I don't immediately see how the viral hypothesis would predict the relapsing-remitting cycle. (Maybe something about the viral replication cycle? But there are some features of MS which don't immediately fit this idea, including the fact that lesion volume doesn't grow exponentially, and the irregularity of relapse occurrences.)

      Transition to SPMS/DMT inefficacy in progressive disease: MD gave a link above, though obviously there are still a lot of details to fill in for the autoimmune account. This not really explained by your viral theory though: the claim that the virus learns to expand independent of the immune system is completely stipulative. You're making the claim that the virus's infection mechanism evolves within the lifetime of a human — and not just for a single human, but systematically, for everyone with MS. This is…pretty bizarre and doesn't seem very evolutionarily stable. Are there any other cases in biology where something similar occurs?

    • Any infection will have some form of activation on white blood cells and many relapses occur after infections, you get colds all the time.

    • MD 11:13: Yes, sure, but unless I've missed something the explanations for this under the autoimmune account are quite handy-wavy. The actual mechanisms by which an infection upregulates autoimmune activity are unknown.

      This isn't evidence *against* the autoimmune account, but it doesn't qualify as evidence in favor of it either.

    • The mechanism by which…..not true there are things such as super antigens how pathogens can activate T cels however the actual mechanisms will only be identified when autoimmune mechanism driven treatments prove positive.

      Immune tolerance will Ihowever fail whilst people ignore our findings that the number of immune clels need to be depleted before tolerance is attempted.

    • MD 3:34: Thank you, is there any evidence that superantigens are triggering relapses during common infections?

    • "All models are wrong, but some are useful" George P.Box. I guess my proposal is not an exception. All I want here it to trigger a stimulant discussion, and Thank to Anon 10pm, it is.

      "The onset of the disease is not much of a mystery" is there an experimental proof of that? Also I could not avoid to notice that a virus is involved here. Do you have an hypothesis on which one?

      I agree with you this viral theory does not say much more on the relapsing-remitting cycle (that is why i put it on the mddle of my list ;). But things like Herpes have also a relapse-remitting cycle and it is caused by a virus.

      On the progressive aspect, Here again, an hypothesis. The analogy about crowded trains is elegant but does not convince me (and invoking fMRI and its horrible latency is not a proof for me). Now, every humans including MSers have something in common. They get old with time. Their cells get older, we do not know exactly why but there are many obvious signs of it (e.g. smaller telomeres). So yeah I am making the proposition that the effect of a virus change with time. Not such a big claim 😉 this is why we vaccinate old people against the flu.

      I'll end with another quote. I love this one and had it on my desk during my PhD as a reminder, "The worst enemy of Science is not ignorance, it is knowledge. To be precise the illusion of knowledge because when you think you know something you stop searching". I would say that medical research is a special case even more evident because you cannot stop searching until someone is fully cured. This is not the case so I guess we should continue searching and be open/discuss all propositions.

    • Guess that the BBC anecdote might be a good reason to continue this discussion? Or you just pooh-pooh this idea 😉

  • Interesting how this study claims that 78.5% of patients in the study experienced improvements when all the stuff I found previously while researching Fampridine to see if it was worth trying stated from other trials that it worked for around 65% of patients.
    Unfortunately I was one of the 35% it didn't work for – it just made my MS related constipation a whole lot worse………
    It didn't add any speed to efforts to get to the loo when dealing with MS related bladder urgency either!

    • Anon at 1.41pm again
      To XorXoR
      Constipation is listed in the manufacturer’s Patient Info sheet as one of the common side effects. Yes – I had MS related constipation prior to taking Fampridine, but it got a whole lot worse while on Fampridine and then returned to “normal” after stopping the drug.

      All of my research prior to trying Fampridine told me that most responders will get a result within 2 to 6 weeks, usually improvement (if it is going to happen) is evident by the end of four weeks. I gave it seven weeks, and then in consultation with my neuro stopped taking it, as I had no walking improvement at all, and the constipation was so bad it was not worth giving it even another week more to see if I was a responder. I had also been advised that using any of the various constipation remedies which work by causing bowel “irritation” would not be a good idea as if the constipation is a result of nerve signals not getting through because of MS lesions they would just end up making me feel very bad indeed. I felt a bit like I was turning into the Monty Python character who exploded after unwisely consuming one “eensy teensy after-dinner mint”!!!

      Maybe Team G could do a Clinicspeak post on practical ways of dealing with MS related constipation? My MS nurse and the continence nurse advised me that just bulking up with lots of extra fibre is not necessarily the solution and can sometimes make things worse – but they didn’t really have much to offer in the way of other options. Life would certainly be a bit more comfortable if there were some workable options I could try.

  • As anonymous said, the effectivity rate of 78.5% is higher than the other studies I have read.
    Having said that, I believe it is working for me. When I first started taking it, I had many of the side effects listed (I am a small women, so potentially I needed a ramp up as I did with my DMT) . More so, was effects not listed – my walking became more labored and I generally was not feeling well. However at about 2 months, all side effects subsided. I feel well and am walking faster. Prescription just renewed.

  • Sorry to read that. Sadly MS do not need medication's side effect to worsen. Why do you think Fampridine constipated you more? Did it reverse when you stopped Fampridine? If not, it might be because of MS more than because of a medication.

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